Article Text

Download PDFPDF
Erdheim–Chester disease associated with a novel, complex BRAF p.Thr599_Val600delinsArgGlu mutation
  1. Jacqueline May Bentel1,2,
  2. Marc Andrew Thomas2,3,
  3. Jamie John Rodgers2,
  4. Mahreen Arooj4,
  5. Elin Gray5,
  6. Richard Allcock6,7,
  7. Soraya Fermoyle1,
  8. Ricardo Luis Mancera4,
  9. Paul Cannell8,
  10. Jeremy Parry1
  1. 1 Anatomical Pathology, PathWest Laboratory Medicine, Fiona Stanley Hospital, Murdoch, Australia
  2. 2 Anatomical Pathology, PathWest Laboratory Medicine, Royal Perth Hospital, Perth, Australia
  3. 3 PathWest Molecular Anatomical Pathology, QEII Medical Centre, Nedlands, Australia
  4. 4 School of Biomedical Sciences, Curtin Health Innovation Research Institute and Curtin Institute for Computation, Curtin University, Perth, Australia
  5. 5 School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
  6. 6 Translational Cancer Pathology Laboratory, Pathwest Laboratory Medicine, QEII Medical Centre, Nedlands, Australia
  7. 7 School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia
  8. 8 Haematology, PathWest Laboratory Medicine, Fiona Stanley Hospital, Murdoch, Australia
  1. Correspondence to Dr Jacqueline May Bentel, Jacky.Bentel{at}


BRAF mutation testing to determine eligibility for treatment with vemurafenib was performed on archival skin lesions of a 54-year-old patient diagnosed with Erdheim–Chester disease (ECD) in 1999. Sanger sequencing of DNA extracted from a 2008 skin lesion identified two non-contiguous base substitutions in BRAF, which were shown by next-generation sequencing (NGS) to be located in the same allele. Due to its long-standing duration, molecular evolution of disease was possible; however, both Sanger and NGS of a 2000 skin lesion were unsuccessful due to the poor quality of DNA. Finally, droplet digital PCR using a probe specific for this novel mutation detected the complex BRAF mutation in both the 2000 and 2008 lesions, indicating this case to be ECD with a novel underlying BRAF p.Thr599_Val600delinsArgGlu mutation. Although well at present, molecular modelling of the mutant BRAF suggests suboptimal binding of vemurafenib and hence reduced therapeutic effectiveness.

  • Haematology (incl blood transfusion)
  • Oncology

Statistics from


  • Contributors JMB analysed sequencing results, collated the data and wrote the manuscript. JJR performed the Sanger sequencing and NGS library preparation. MAT performed the Sanger sequencing and designed the ddPCR probe. RA analysed the NGS. EG performed and analysed the ddPCR. RLM and MA performed the protein modelling. SF performed and reviewed the histopathology. PC (clinically) managed the case and provided the case presentation. JP managed the case. All authors were involved in the design of aspects of the analysis of this case and reviewed and approved the final version of the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.